Upregulation of epidermal growth factor receptor (EGFR) and subsequent increases in extracellular-regulated kinase (ERK) and Akt signaling are implicated in prostate cancer progression. Impaired endocytic downregulation of EGFR also contributes to oncogenic phenotypes such as metastasis. Thus, understanding the roles of divergent signaling pathways in the regulation of EGFR trafficking and EGFRdriven invasive migration may enable the development of more effective therapies. In this study, we use the human prostate cancer cell lines, DU145 and PC3, to investigate the effects of both the ERK and Akt pathways on epidermal growth factor (EGF)-mediated EGFR signaling, trafficking and cell motility. We show that DU145 and PC3 cells overexpress EGFR and migrate in a ligand (EGF)-dependent manner. Next, we show that pharmacological inhibition of ERK (but not Akt) signaling enhances EGFinduced EGFR activation, ubiquitination and downregulation, and may lead to enhanced receptor turnover. These findings negatively correlate with ERK-mediated threonine phosphorylation of EGFR, implicating it as a possible mechanism. Further, we uncover that EGF promotes disassembly of cell-cell junctions, downregulation of E-cadherin and upregulation of the transcriptional repressor, Snail, typical characteristics of epithelial-mesenchymal transition (EMT). These effects are dependent on activation of Akt, as inhibition of Akt signaling abolishes EGF/EGFR-driven cell migration and EMT. Knockdown of endogenous Snail also prevents EGFR-mediated downregulation of E-cadherin, EMT and cell migration. Surprisingly, inhibition of the ERK pathway augments EGFR-dependent motility, occurring concomitantly with elevation of EGF-induced Akt activity. Collectively, our results suggest that EGF-triggered ERK activation has profound feedback on EGFR signaling and trafficking by EGFR threonine phosphorylation, and Akt has a pivotal role in EGFR-mediated cell migration by activating EMT. More important, our results also suggest that therapeutic targeting of ERK signaling may have undesirable outcomes (for example, augmenting EGFR-driven motility).

Pudendal neuralgia is a painful, neuropathic condition involving the dermatome of the pudendal nerve. This condition is not widely known and often unrecognized by many practitioners. The International Pudendal Neuropathy Association (tipna.org) estimates the incidence of this condition to be 1/100,000; however, most practitioners treating patients with this condition feel the actual rate of incidence may be significantly higher. Currently, there is fair paucity of medical literature and scientific evidence in the diagnosis and treatment of pudendal neuralgia. Diagnosis of this condition is based on the utilization of Nantes Criteria, in conjunction with clinical history and physical findings. CT-scan guided nerve blocks are also employed, by this author, to provide additional information. Subsequent treatment of pudendal neuralgia is medical and well as surgical, with Physical Therapy a key component to all aspects of treatment. The goal of this paper is to present evidence based information, as well as personal clinical experience, in treating approximately 200 patients with pudendal neuralgia.

Aim:The adverse effects of local anesthetics (LAs) on wound healing at surgical sites have been suggested, and may be related to their cytotoxicity. This study was aimed to compare the cellular toxicity of bupivacaine and lidocaine (two well-known LAs), and to explore the molecular mechanism(s). Methods: Toxicity of bupivacaine and lidocaine was assessed in cultured mouse C2C12 myoblasts by cell viability and apoptosis assays. effects of LAs on extracellular signal-regulated kinase (erK) and protein kinase b (Akt) activation, which are essential for cell proliferation and survival, were evaluated by immunoblotting. Results: both LAs, especially bupivacaine, prevented cell growth and caused cell death in a dose-dependent manner. The half maximal inhibitory concentrations (IC 50 ) for bupivacaine and lidocaine were 0.49±0.04 and 3.37±0.53 mmol/L, respectively. When applied at the same dilutions of commercially available preparations, the apoptotic effect induced by bupivacaine was more severe than that of lidocaine in C2C12 cells. Furthermore, bupivacaine significantly diminished the ERK activation, which may underlie its anti-proliferative actions. both LAs suppressed Akt activation, which correlated with their effects on apoptosis. Conclusion: Our study demonstrated that, when used at the same dilutions from clinically relevant concentrations, bupivacaine is more cytotoxic than lidocaine in vitro. Anti-proliferation and cell death with concomitant apoptosis mediated by bupivacaine may offer an explanation for its adverse effects in vivo (eg slowing wound healing at the surgical sites). A less toxic, long-acting anesthetic may be needed.

Objective-To describe the effect of lifting maneuver and quantity of weight lifted on the generation of intra-abdominal pressure.Study Design-Forty-one women undergoing urodynamic evaluation performed four lifting maneuvers, each while lifting 0, 2.5, 5, 10, and 15 kg. The lifting maneuvers were routine activities including squatting with and without assistance, lifting from a counter and receiving weight. Pressure was recorded with a rectal microtip catheter. Each lift was performed twice and the average pressure change was analyzed.Results-Controlling for potential confounding variables, repeated-measures ANOVA revealed a significant interaction between lift weight and lift maneuver (p= <0.001). Squatting was associated with generation of higher intra-abdominal pressure than lifting from a counter or receiving weights into outstretched arms (p= <0.001). Lifting ≥2.5 kg resulted in significant changes in intra-abdominal pressure regardless of lift maneuver (p= <0.001).Conclusions-Both lifting maneuver and quantity of weight should be considered when counseling patients regarding postoperative lifting.

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